A multi-scale strategy is proposed to develop, couple, apply, and validate multimodality imaging and physics modeling of resolvable and sub-resolvable scales in human respiration. High-resolution computed tomography (HRCT) will be used to characterize the "macroscale" convective range of the lung. Microscopic computed tomography (.CT), and confocal microscopy (CLSM), will be used to characterize the "microscale" global and cellular architectures of the respiratory units. Multiphase computational fluid dynamics and quasi-one-dimensional functional modeling will be used to simulate the multi-component fluid mechanics at the macro- and micro-scales, respectively. Software infrastructure and two-phase fluid mechanics models will be developed to address the coupling between the physics at these two scales. Model predictions will be validated against experimental and clinical data from the literature. A novel and critical element of the proposed research is that the interfaces between functional biological scales will be developed using recent dimension-reducing coupling strategies developed in the nuclear reactor safety/simulation community, and multidisciplinary data-exchange standards developed in the aerospace sciences community. Coupling technologies will be developed between macro- and microscales, and between imaging and physical modeling; these will yield a system-level model that accommodates the critical two-way coupling between convective respiration physics and uptake, deposition, and disease-state morphology. Such an integrated approach will elucidate heretofore inaccessible physical understanding, dependencies, and treatment implications. The coupling software to be developed will be modular and open-source so other investigators can "plug-in" their models at the macro- and micro-scales, and/or evolve the system to other organs or human systems such as the liver or kidney. The ultimate public health goal of the research is improved understanding of respiratory function and disease, and evaluation/assessments of the effects of therapies, injury, surgical intervention, and aging on lung structure and function. The physics-based coupling between multiple scales is a critical step towards a complete integrated physiological model of the human respiratory system: a "virtual human lung."